Influence of BDNF Val66Met polymorphism on excitatory-inhibitory balance and plasticity in human motor cortex.

OBJECTIVE: While previous studies showed that the single nucleotide polymorphism (Val66Met) of brain-derived neurotrophic factor (BDNF) can impact neuroplasticity, the influence of BDNF genotype on cortical circuitry and relationship to neuroplasticity remain relatively unexplored in human. METHODS: Using individualised transcranial magnetic stimulation (TMS) parameters, we explored the influence of the BDNF Val66Met polymorphism on excitatory and inhibitory neural circuitry, its relation to I-wave TMS (ITMS) plasticity and effect on the excitatory/inhibitory (E/I) balance in 18 healthy individuals. RESULTS: Excitatory and inhibitory indexes of neurotransmission were reduced in Met allele carriers. An E/I balance was evident, which was influenced by BDNF with higher E/I ratios in Val/Val homozygotes. Both long-term potentiation (LTP-) and depression (LTD-) like ITMS plasticity were greater in Val/Val homozygotes. LTP- but not LTD-like effects were restored in Met allele carriers by increasing stimulus intensity to compensate for reduced excitatory transmission. CONCLUSIONS: The influence of BDNF genotype may extend beyond neuroplasticity to neurotransmission. The E/I balance was evident in human motor cortex, modulated by BDNF and measurable using TMS. Given the limited sample, these preliminary findings warrant further investigation. SIGNIFICANCE: These novel findings suggest a broader role of BDNF genotype on neurocircuitry in human motor cortex.

Repetitive transcranial magnetic stimulation plus standardized suggestion of benefit for functional movement disorders: an open label case series.

BACKGROUND: We studied suggestion of benefit combined with motor cortex and premotor cortex repetitive transcranial magnetic stimulation (rTMS) in chronic (>2 years) FMDs. METHODS: Patients were identified from our patient records who had clinically definite FMDs and had undergone neuropsychiatric evaluation. Those with chronic FMDs were offered open-label rTMS over the dominant motor cortex. If they failed to improve they received dominant premotor cortex rTMS. The primary outcome was change from baseline to post-rTMS in quality of life measured by the World Health Organization Quality of Life Brief (WHOQOL-BREF) scale. Secondary outcomes were subject and investigator global impression of change (GIC), blinded Rush psychogenic movements rating scale, Barbers suggestibility scale, baseline expectation of benefit scale, and adverse effects. RESULTS: Six subjects were enrolled. For the primary outcome, there was significant improvement in the physical domain scores but significant reduction in psychological domain scores after premotor cortex rTMS compared to baseline and after motor cortex rTMS. There was no significant change between baseline and motor cortex rTMS or in any other domain after premotor cortex rTMS. Secondary outcome measures showed no meaningful change. Transient headache and worsening of FMD symptoms were the most common adverse effects observed. CONCLUSION: rTMS combined with strong suggestion of benefit provided dissonant results after premotor cortex rTMS with improvement in physical quality of life but reduction in psychological quality of life. These results serve to underscore the complex nature of FMDs where the overt physical manifestation is but one part of a comprehensive neuropsychological syndrome.

Impaired interhemispheric inhibition in writer's cramp.

OBJECTIVES: Reduced cortical inhibition is a feature of focal hand dystonia and this likely contributes to excessive muscle contractions. Inhibition from the opposite hemisphere, known as interhemispheric inhibition (IHI), was studied bidirectionally in 7 right-handed patients with writer's cramp (WC) and age-matched healthy controls in a cross-sectional physiologic study. METHODS: IHI was measured with paired transcranial magnetic stimulation with the conditioning stimulus applied to the motor cortex and the test stimulus applied to the contralateral motor cortex. Surface EMG was measured in right and left first dorsal interosseous muscles during rest, and while holding a pen between the thumb and index finger at 20% maximum voluntary contraction with the right dystonia-affected hand. The time course and magnitude of IHI was studied at interstimulus intervals of 6, 8, 10, 12, 30, 40, and 50 msec between the conditioning stimulus and test stimulus. RESULTS: In WC at rest, IHI was significantly reduced in the dystonia-affected right hand (IHI from right to left motor cortex) at both short (SIHI, 10-12 msec) and long (LIHI, 30-40 msec) intervals compared to the unaffected hand. Compared to controls, SIHI and LIHI were reduced in the dystonia-affected hand only. There was no difference in IHI between controls and WC during the task of holding a pen. CONCLUSIONS: In WC, both SIHI and LIHI are reduced in the dystonia-affected hand compared to the unaffected hand and to healthy controls. Impaired IHI may contribute to excessive muscle contraction in WC.

Impaired presynaptic inhibition in the motor cortex in Parkinson disease.

OBJECTIVE: Intracortical inhibition in the motor cortex may be measured with short interval intracortical inhibition (SICI), likely mediated by GABA(A) receptors, and long interval intracortical inhibition (LICI), likely mediated by GABA(B) receptors. Separate neuronal populations mediate SICI and LICI, and LICI inhibits SICI, likely through GABA(B) mediated presynaptic inhibition. The purpose of this study was to test the hypothesis that cortical presynaptic inhibition in Parkinson disease (PD) is impaired. METHODS: Eleven patients with PD were studied at rest both OFF and ON dopaminergic medications and the results were compared to nine healthy, age-matched controls. Motor evoked potentials were recorded from the first dorsal interosseous muscle and a triple-stimulus transcranial magnetic stimulation paradigm was used to evaluate SICI in the presence of LICI. The interstimulus interval (ISI) for SICI was 2 msec and LICI was studied at 100 (LICI(100)) and 150 msec (LICI(150)) ISIs. RESULTS: There was no difference in SICI between the controls and PD ON and PD OFF groups. LICI(100) was stronger than LICI(150) and both were reduced in the PD ON and OFF groups. LICI(100) led to a much greater reduction in SICI in the control group compared to both the PD OFF and ON groups. LICI(150) caused no significant change in SICI with no significant difference between the controls and PD OFF and PD ON groups. CONCLUSIONS: The inhibitory effect of long interval intracortical inhibition on short interval intracortical inhibition, likely representing presynpatic inhibition in the motor cortex, is decreased in Parkinson disease and may be a nondopaminergic feature of the disease.

Subthalamic nucleus stimulation modulates afferent inhibition in Parkinson disease.

BACKGROUND: Peripheral sensory stimulation at the wrist inhibits the motor cortex as measured by transcranial magnetic stimulation at interstimulus intervals of approximately 20 ms (short latency afferent inhibition [SAI]) and 200 ms (long latency afferent inhibition [LAI]). Previous studies suggested that reduced SAI in Parkinson disease (PD) reflects adverse effect of dopaminergic medications and reduced LAI may be related to nondopaminergic manifestations of PD. We hypothesize that subthalamic nucleus (STN) deep brain stimulation (DBS) may correct these deficiencies. METHODS: We studied the effects of STN DBS on SAI and LAI in seven PD patients and age-matched controls. PD patients were studied in an off medication followed by an on medication session, with the stimulator switched on or off in random order in each session. RESULTS: In the on medication session, SAI was reduced in the stimulator off condition and was restored by STN DBS. LAI was partially normalized by STN DBS in the medication on condition. CONCLUSIONS: Subthalamic nucleus (STN) stimulation improves short latency afferent inhibition, suggesting that it could normalize pathways that are adversely affected by dopaminergic medications. The effect of STN stimulation on long latency afferent inhibition suggests that it may influence nondopaminergic pathways involved in sensorimotor integration.

Changes in motor cortex excitability with stimulation of anterior thalamus in epilepsy.

BACKGROUND: Deep brain stimulation (DBS) is an effective treatment for movement disorders and pain. Recently, bilateral DBS of the anterior nucleus of thalamus (AN) was performed for the treatment of intractable epilepsy. This surgery reduced seizure frequency in an initial group of patients. However, its physiologic effects on the cortex and mechanisms of action remain poorly understood. Different classes of antiepileptic drugs (AEDs) have distinct effects on the excitatory and inhibitory circuits in the motor cortex, which can be studied noninvasively by transcranial magnetic stimulation (TMS). OBJECTIVE: To examine the effects of bilateral AN DBS on motor cortex excitability in epilepsy and compare these to the known effects of AEDs. METHODS: Cortical excitability was assessed in five medicated epilepsy patients with bilateral stimulators implanted in the anterior thalamus and nine healthy controls. Single and paired TMS were used to examine cortical inhibitory and facilitatory circuits. Electromyography was recorded from the dominant hand, and TMS was applied over the contralateral motor cortex. Patients were studied during DBS turned off (OFF condition), DBS with cycling stimulation mode (1 minute on, 5 minutes off; CYCLE), and DBS with continuous stimulation (CONTINUOUS) in random order on 3 consecutive days. RESULTS: Motor thresholds were increased in the patients regardless of DBS condition. Active short-interval intracortical inhibition (SICI) was significantly reduced in the OFF and CYCLE conditions but returned toward normal levels in the CONTINUOUS condition. Rest SICI, long interval intracortical inhibition, and silent period duration were unchanged. CONCLUSIONS: Increased short-interval intracortical inhibition with continuous deep brain stimulation (DBS) suggests that thalamic DBS might drive cortical inhibitory circuits, similar to antiepileptic drugs that enhance gamma-aminobutyric acid inhibition.

Changes in cortical excitability with thalamic deep brain stimulation.

BACKGROUND: Deep brain stimulation (DBS) is an effective treatment for several movement disorders. However, its mechanism of action is largely unknown. Both lesioning and DBS of the ventralis intermedius (VIM) nucleus of thalamus improve essential tremor. Although DBS was initially thought to inhibit the target neurons, recent studies suggest that DBS activates neurons. OBJECTIVE: To test the hypothesis that thalamic DBS activates the target area in patients with essential tremor. METHODS: Cortical excitability was assessed in seven unmedicated patients with essential tremor using unilateral stimulators implanted in the VIM of the dominant hemisphere and in 11 healthy controls using transcranial magnetic stimulation (TMS). Patients were studied during optimal DBS (ON condition), half the optimal frequency (HALF), and with DBS off (OFF) in random order. Tremor was assessed after a change in DBS setting. Electromyography was recorded from the dominant hand, and TMS was applied over the contralateral motor cortex using single and paired pulses to elicit motor evoked potentials (MEPs). MEP recruitment was determined using stimulus intensities from 100% to 150% of motor threshold. RESULTS: Tremor scores were significantly improved with DBS ON. Analysis of variance showed a significant interaction between condition (ON, HALF, OFF, Normal) and stimulus intensity on MEP amplitude. During DBS ON MEP amplitudes were significantly higher compared with controls at high but not at low TMS intensities. CONCLUSION: Because the ventralis intermedius (VIM) projects directly to the motor cortex, the high motor evoked potential amplitude with deep brain stimulation ON suggests that VIM DBS activates rather than inhibits the target area.

Thalamic deep brain stimulation activates the cerebellothalamocortical pathway.

To investigate the mechanism of action of deep brain stimulation (DBS), the authors studied the effects of thalamic DBS on the cerebellothalamocortical (CTC) pathway. With DBS turned off, excitability of the CTC pathway was reduced. Turning DBS on resulted in facilitation of the CTC pathway. Therefore, thalamic DBS appears to activate rather than inhibit the target area.